The metastatic microenvironment is receiving increasing attention as a target for new breast cancer therapies. The sympathetic nervous system (SNS) is a component of this microenvironment, and recent studies indicate that SNS activity may support tumor progression through a number of pathways. The proposed research seeks to define the cellular and molecular mechanisms by which SNS activity in metastatic target organs may enhance breast cancer metastasis during chronic stress. Specifically, these studies will utilize novel real-time imaging analyses of a mouse model of spontaneous metastasis from a primary tumor to (a) determine the role of SNS signaling in stress-enhanced breast cancer metastasis, and (b) investigate the role of chemokine receptor signaling in stress-enhanced breast cancer metastasis. We will examine the role of the SNS in chronic stress effects on metastasis by experimentally blocking SNS signaling at the level of nerve fibers or beta-adrenergic receptors. Similarly, we will investigate if experimentally inhibiting chemokine signaling reduces stress-enhanced metastatic progression. These studies will define the molecular and cellular mechanisms by which chronic stress modulates metastatic progression, from systemic dissemination from a clinically relevant primary tumor to arrest in distant organs. Results of these studies will establish the mechanistic foundation for new interventions that target the SNS as an upstream mediator of multiple metastasis-associated processes, and define a system for the study of other behavioral and psychological factors on breast cancer metastasis. Such interventions would complement current anti-tumor therapies by specifically targeting the neural component of the metastatic microenvironment. PUBLIC HEALTH RELEVANCE: Tumor metastasis represents the major cause of morbidity and mortality in breast cancer. The studies described here will assess the molecular and cellular mechanisms for the effects of chronic stress on metastatic progression. These studies will lay the foundation for new interventions that seek to protect stressed individuals from the adverse effects of stress biology on malignant disease.